The current investigation provided the first more detailed study into the comparative histopathological and hematology changes induced by melanin extracted (ME) from Sepia pharaonis' ink  in both albino and pigmented mice. Additionally, the role of glutathione (GSH) as a melanin-control drug has been investigated when administrated simultaneously with ME. S. pharaonis' ME had harmful effects for the mammalian digestive system at the current dose (25 mg/kg). In hepatocytes, it caused inflammation with lymphocyte aggregation from damaged cells and vacuolation deformation at the stomach, colon, liver, and spleen. However, the skin showed an increase in hair follicle number and some inflammations. The administration of ME showed an increase in blood platelets and elevation of lymphocytes. The co-administration of GSH simultaneously with ME reduced some of these abnormalities. ME showed a greater influence on the treated spleen and skin compared with those treated with both ME and GSH. Additionally, the effect of GSH treatment concurrently with ME controlled these alterations and decreased inflammation, as well as vacuolation. The present study highlights some in vivo negative parameters produced by ME extracted from S. pharoanis, and this may be useful for people who eating foods containing ink. Additionally, more investigations are needed to illustrate the importance of ME when it is used in skincare cosmetics.